Application in response to Notice Number: NOT-OD-09-058 Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Our laboratory has focused on discovering genes that are important for regulating iron homeostasis, with the overall goal of understanding human iron disorders. We have used animal models with inherited iron deficiency anemia to identify key components of iron transport pathways. We have also identified genes defective in human patients with inherited iron disorders. In the first cycle of the parent grant, we turned our attention to the discovery of novel genes that play more subtle roles in iron biology, reasoning that mouse genetics could be used as a tool not only to discover major components of iron transport and regulatory pathways, but also minor components that become important as modifiers of iron status. The technology to carry out modifier gene mapping experiments has improved over the past five years, allowing novel approaches to this problem. A pending competing renewal application for the parent grant covers two gene discovery approaches to identify additional candidate genes that directly or indirectly modulate tissue iron accumulation in the liver and spleen. In this Supplement, we propose to complement those studies with hypothesis-directed studies of the roles of two known genes - DMT1 and TFR1 - in another tissue that is important in iron homeostasis. We will use novel, unpublished mouse models, already developed in our laboratory, to investigate the homeostatic implications of altering DMT1 and TFR1 expression in the intestine. These complementary approaches should enhance our understanding of iron homeostasis and, importantly, expand our understanding of clinical variability in the incidence and severity of iron disorders. ) PUBLIC HEALTH RELEVANCE: Iron overload and iron deficiency disorders are common in human populations. The projects described in this competitive supplement focus on the characterization of novel mouse models transgenic for genes important in the regulation of iron homeostasis. Completion of this work will provide additional knowledge regarding genes involved in iron regulation. This information will help identify possible therapeutic targets for the treatment of iron disorders in humans.